Zilt - instructions for use, dose, side effects, contraindications

core: active substance: clopidogrel hydrogensulfate 97.875 mg, based on clopidogrel 75,000 mg; Excipients: lactose, anhydrous 108,125 mg, microcrystalline cellulose 30.00 mg, pregelatinized starch 12.00 mg, macrogol 6000 8.00 mg, castor oil hydrogenated 4.00 mg;

sheath: hypromellose 6cp 5.60 mg, titanium dioxide (E171) 1.46 mg, talc 0.50 mg, iron dye red oxide (E 172) 0.04 mg, propylene glycol 0.40 mg.

Description:

Round, slightly biconcave tablets, covered with a film membrane of pink color.

* Cross-sectional view: white or almost white, rough mass with a film cover of pink color.

Pharmacotherapeutic group:antiplatelet agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. The active metabolite of clopidogrel selectively inhibits binding adenosine diphosphate (ADP) with P2Y_I2 receptors of platelets and subsequent ADP-mediated activation of glycoprotein GPIIb /IIIbut complex, which leads to inhibition of platelet aggregation.

Suppression of platelet aggregation is irreversible and continues throughout the cell life cycle (about 7-10 days), so the rate of recovery of normal platelet function corresponds to the rate of their renewal. Aggregation of platelets induced by other agonists other than ADP is also inhibited due to blockade of enhanced platelet activation by ADP.

The active metabolite is formed by the action of CYP450 isoenzymes, some of which may be polymorphic or may be inhibited by other drugs, so that adequate inhibition of platelet aggregation is not observed in all patients.

In the treatment of clopidogrel at a dose of 75 mg per day from the first day of therapy, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases for 3-7 days and then reaches a constant level (when the equilibrium state is reached). In the equilibrium state, the degree of inhibition of platelet aggregation with clopidogrel at a dose of 75 mg per day, on average, was 40% to 60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually returned to baseline values, on average, for 5 days. Clopidogrel allows to prevent the development of atherothrombotic complications in patients with atherosclerotic lesions of vessels of any localization, especially with damage to the cerebral, coronary or peripheral arteries.

Pharmacokinetics:

Suction

After a single and repeated oral administration at a dose of 75 mg per day clopidogrel quickly absorbed. Mean values of maximum concentration (C_m_Oh) of unchanged clopidogrel in blood plasma (2.2-2.5 ng / ml after ingestion of a single dose of 75 mg) are reached after about 45 minutes. According to the study of kidney excretion of clopidogrel metabolites, the degree of absorption is approximately 50%.

Distribution

Clopidogrel and its main circulating in blood plasma inactive metabolite reversibly bind to human plasma proteins in conditions in vitro (98% and 94% respectively). This bond is unsaturated in a wide range of concentrations.

Metabolism

Clopidogrel is actively metabolized in the liver. In conditions in vitro and in vivo clopidogrel is metabolized in two ways: the first is mediated by esterases and leads to hydrolysis with the formation of an inactive metabolite, a carboxylic acid derivative (85% of the circulating metabolites), and the other is catalyzed by various cytochrome P450 isoenzymes. at first clopidogrel is converted to an intermediate metabolite - 2-oxo-clopidogrel. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel-thiol clopidogrel derivative.In in vitro conditions, this route is mediated by isoenzymes CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol clapidogrel metabolite, isolated under conditions in vitro, quickly and irreversibly interacts with platelet receptors, blocking their aggregation.

FROM_m_Oh active metabolite in blood plasma after taking a loading dose (300 mg) of clopidogrel is twice as high as C_m_Oh after 4-day use of clopidogrel in a maintenance dose (75 mg / day). FROM_m_Oh in blood plasma is achieved approximately 30-60 minutes after taking the drug.

Excretion

After oral administration ¹⁴FROM-labeled clopidogrel approximately 50% of the total radioactivity is excreted by the kidneys and approximately 46% by the intestine within 120 hours after dosing. After a single oral administration of clopidogrel at a dose of 75 mg, the elimination half-life (T_1/2) is about 6 hours. T_1/2the main circulating in the blood plasma inactive metabolite after a single and repeated application is 8 hours.

Pharmacogenetics

The CYP2C19 isozyme is involved in the formation of both an active metabolite and an intermediate metabolite, 2-oxo-clopidogrel. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, as well as the results of the evaluation of platelet aggregation under ex vivo conditions, differ depending on the genotype of the isoenzyme CYP2C19.

The allele of the CYP2C19 * 1 isoenzyme gene corresponds to a fully functional metabolism, whereas the alleles of the CYP2C19 * 2 and CYP2C19 * 3 isoenzymes are non-functional. Alleles of the CYP2C19 * 2 and CYP2C19 * 3 isoenzymes genes cause a decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid (99%) races. Other alleles associated with a lack or decrease in metabolism are less common and include, but are not limited to, the alleles of the isoenzyme genes CYP2C19 * 4, * 5, * 6, * 7 and * 8.

Patients with a low activity of the isoenzyme CYP2C19 should have the two alleles of the loss-of-function gene mentioned above. According to published studies, the frequency of genotypes with a low activity of the CYP2C19 isoenzyme, accompanied by a decrease in metabolism, is approximately 2% in the representatives of the Caucasoid race, 4% in the Negroid and 14% in the persons of the Mongoloid race. There are tests to determine the genotype of the isoenzyme CYP2C19. According to the study and meta-analysis, which included people with very high, high, intermediate and low activity of the isoenzyme CYP2C19, a significant difference in exposure of the active metabolite and moderate inhibition of ADP-induced platelet aggregation in volunteers with very high, high and intermediate isoenzyme activity CYP2C19 was absent.In volunteers with a low activity of this isoenzyme, the exposure of the active metabolite decreased compared to that of volunteers with high activity of the isoenzyme CYP2C19.

Using clopidogrel at doses of 600 mg loading dose / 150 mg maintenance dose (600 mg / 150 mg) in patients with low metabolism, the exposure of the active metabolite was higher than with the 300 mg / 75 mg treatment regimen. In addition, the degree of inhibition of platelet aggregation was similar to that in the groups of patients with high CYP2C19 isoenzyme activity, who received clopidogrel according to the scheme of 300 mg / 75 mg. However, the dosage regimen of clopidogrel in the group of patients with a low activity of the isoenzyme CYP2C19 is not defined in studies suggesting the study of clinical outcomes. The clinical trials conducted to date have had insufficient sample size to detect differences in clinical outcome in patients with low CYP2C19 isoenzyme activity.

Pharmacokinetics of special groups of patients

The pharmacokinetics of the active metabolite of clopidogrel in specific patient groups (elderly patients, children, patients with impaired renal and hepatic function) has not been studied.

Elderly patients

In elderly volunteers (over 75 years old), when compared with young volunteers, no differences in platelet aggregation and bleeding time were revealed. Dose adjustments in elderly patients are not required.

Impaired renal function

After repeated use of clopidogrel at a dose of 75 mg per day in patients with severe renal dysfunction (CK 5-15 ml / min), the degree of inhibition of ADP-induced platelet aggregation is lower by 25% than in healthy volunteers. However, the degree of lengthening of bleeding time was similar to that of healthy volunteers who received clopidogrel in a dose of 75 mg per day.

Impaired liver function

After using clopidogrel at a dose of 75 mg per day for 10 days in patients with severe liver dysfunction, the degree of inhibition of ADP-induced platelet aggregation and the mean elongation of bleeding time were comparable to healthy volunteers.

Ethnic Features

The prevalence of the alleles of the CYP2C19 isoenzyme genes associated with intermediate or decreased metabolism is different in representatives of different racial / ethnic groups (see Fig.subsection "Pharmacogenetics"). There are limited literature data to assess the genotyping of the isoenzyme CYP2C19 on clinical outcomes for patients of the Mongoloid race.

Indications:

Prevention of atherothrombotic complications:

- in adult patients with myocardial infarction (prescription from several days to 35 days), with ischemic stroke (from 7 days to 6 months old) or with diagnosed occlusive disease of peripheral arteries;

- in adult patients with acute coronary syndrome: no ST segment elevation (unstable angina or Q-free myocardial infarction), including patients who undergo stenting with percutaneous coronary intervention, in combination with acetylsalicylic acid; with the rise of the ST segment (acute myocardial infarction) with drug treatment and the possibility of performing thrombolytic therapy, in combination with acetylsalicylic acid.

Prevention of atherothrombotic and thromboembolic complications, including stroke, with atrial fibrillation (atrial fibrillation)

Adult patients with atrial fibrillation (atrial fibrillation) who have, as a minimum,one risk factor for vascular complications, can not take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid).

Contraindications:

- Hypersensitivity to clopidogrel or any excipients included in the preparation;

- severe liver dysfunction;

- acute bleeding, eg bleeding from a peptic ulcer or intracranial hemorrhage;

- deficiency of lactase, lactose intolerance, glucose-galactose malabsorption syndrome;

- pregnancy and the period of breastfeeding;

- children under 18 years of age (safety and efficacy not established).

Carefully:

- Moderate dysfunction of the liver with a predisposition to bleeding (limited experience of use);

- impaired renal function (limited experience of use);

- pathological conditions that increase the risk of bleeding (including trauma, surgical interventions (see section "Special instructions"));

- diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal and intraocular);

- simultaneous use with non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 inhibitors (COX-2);

- simultaneous use of warfarin, heparin or inhibitors of glycoprotein IIb / IIIa;

- patients with low activity of the isozyme CYP2C19 (when clopidogrel is used in recommended doses, less active metabolite of clopidogrel is formed and its antiplatelet effect is less pronounced, so when using clopidogrel at recommended doses in acute coronary syndrome or percutaneous coronary intervention, the incidence of cardiovascular complications may be higher , than in patients with normal activity of the isoenzyme CYP2C19);

- hypersensitivity to other thienopyridine (eg, ticlopidine, prasugrel) (see section "Special instructions").

Pregnancy and lactation:

Since clinical data on the use of clopidogrel during pregnancy are absent, the drug is not recommended for use in pregnancy. Studies in animals have not revealed a direct or indirect adverse effect on pregnancy, embryo / fetus development, childbirth or postnatal development.

In animal studies, it has been shown that clopidogrel and / or its metabolites are excreted into breast milk. Therefore, if therapy is necessary clopidogrel It is recommended to stop breastfeeding.

Dosing and Administration:

Inside, regardless of food intake, once a day.

Adults and elderly patients with normal activity of the isoenzyme CYP2C19

Myocardial infarction, ischemic stroke or diagnosed occlusive disease of peripheral arteries.

The drug Zilt® is taken in a dose of 75 mg (1 tablet) once a day.

Acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q-wave)

Treatment with Zilt® should be started with a single dose of loading dose (300 mg), and then continued with a 75 mg dose once a day (in combination with acetylsalicylic acid at doses of 75-325 mg per day). Since the use of higher doses of acetylsalicylic acid is associated with a greater risk of bleeding, the recommended dose of acetylsalicylic acid should not exceed 100 mg. The maximum favorable effect is observed by the 3rd month of treatment.The optimal duration of treatment with this indication is not officially defined. The results of clinical studies confirm the advisability of taking clopidogrel up to 12 months after the development of acute coronary syndrome without ST segment elevation.

Acute coronary syndrome with ST segment elevation (acute myocardial infarction) with drug treatment and the possibility of thrombolytic therapy, in combination with acetylsalicylic acid.

The drug Zilt® should be taken at a dose of 75 mg (1 tablet) once a day, starting with a loading dose, in combination with acetylsalicylic acid in combination or without thrombolytics. For patients older than 75 years, treatment with Silt® should be performed without the use of a loading dose. Combination therapy is started as soon as possible after the onset of symptoms and continues for at least 4 weeks. The effectiveness of combined therapy with clopidogrel and acetylsalicylic acid for more than 4 weeks in such patients has not been studied.

Atrial fibrillation (atrial fibrillation)

The drug Zilt® is prescribed in a dose of 75 mg once a day.In combination with clopidogrel, you should begin therapy and then continue taking acetylsalicylic acid at a dose of 75-100 mg per day.

If the patient missed the next dose:

- if less than 12 hours have elapsed after missing the next dose, you should immediately take the missed dose of Zilt® and then take the next dose at the usual time;

- if more than 12 hours passed after missing the next dose, the next dose should be taken at the usual time; at the same time, do not double the dose.

Adults and elderly patients with genetically determined reduced activity of the isoenzyme CYP2C19

The low activity of the isoenzyme CYP2C19 is associated with a decrease in the antiplatelet effect of clopidogrel. The use of Zilt® at higher doses (loading dose 600 mg, then 150 mg once daily) in patients with a low activity of the isoenzyme CYP2C19 leads to an increase in the antiplatelet effect of clopidogrel (see the section "Pharmacokinetics"). However, clinical studies on clinical outcomes have not established an optimal dosing regimen for clopidogrel in patients with reduced metabolism due to the genetically determined low activity of the CYP2C19 isoenzyme.

Special patient groups

Elderly patients

Impaired renal function

Ethnic Features

Prevalence isozyme alleles CYP2C19, associated with the intermediate or decreased metabolism, is characterized in representatives of different racial / ethnic groups (see. Subsection "pharmacogenetics").There are limited literature data to assess the genotyping of the isoenzyme CYP2C19 on clinical outcomes for patients of the Mongoloid race.

Gender Effects

When comparing the pharmacodynamic properties of clopidogrel in men and women, a less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in lengthening the bleeding time. When comparing clopidogrel with acetylsalicylic acid in patients at risk of developing ischemic complications, the frequency of clinical outcomes, other side effects and deviations from the norm of clinical and laboratory indicators was the same for both men and women.

Side effects:

The safety of clopidogrel was investigated in patients who received clopidogrel therapy for 1 year or more. The safety of clopidogrel at a dose of 75 mg per day was comparable with that of acetylsalicylic acid at a dose of 325 mg per day, regardless of age, sex, and race. The undesirable reactions observed in clinical studies are listed below. In addition, spontaneous reports of unwanted reactions are indicated.

In clinical studies and post-marketing surveillance of clopidogrel, bleeding was reported most frequently, mainly during the first month of therapy.

Classification of the frequency of development of side effects of the World Health Organization (WHO): very often ≥1/10; often from ≥1/100 to <1/10; infrequently from ≥1/1000 to <1/100; rarely from> 1/10000 to <1/1000; very rarely <1/10000; the frequency is unknown, can not be estimated from the available data.

Violations from the blood and lymphatic system: infrequently: thrombocytopenia, leukopenia, eosinophilia; rarely: neutropenia, including cases of severe neutropenia; very rarely: thrombotic thrombocytopenic purpura (see section "Special instructions"), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia.

Immune system disorders: very rarely: serum sickness, anaphylactoid reactions; frequency unknown: cross-reactive hypersensitivity to thienopyridines (eg, ticlopidine, prasugrel).

Disorders of the psyche: very rarely: confusion, hallucinations.

Disturbances from the nervous system: infrequently: intracranial hemorrhage (several cases have been reported with a fatal outcome), headache, dizziness and paresthesia; very rarely: a violation of taste perception.

Disturbances on the part of the organ of sight: infrequently: hemorrhage into the eyeball (conjunctiva, tissue and retina of the eye).

Hearing disorders and labyrinthine disorders: rarely: vertigo.

Vascular disorders: often: hematoma; very rarely: serious bleeding from the operating wound, vasculitis, lowering blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs: often: epistaxis; very rarely: bleeding from the respiratory tract (hemoptysis, pulmonary bleeding), bronchospasm, interstitial pneumonitis.

Disorders from the gastrointestinal tract: often: gastrointestinal bleeding, diarrhea, abdominal pain, indigestion; infrequently: a stomach ulcer and duodenal ulcers, gastritis, vomiting, nausea, constipation, bloating; rarely: retroperitoneal hemorrhage; very rarely: gastrointestinal and retroperitoneal hemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative colitis or lymphocytic colitis), stomatitis.

Disturbances from the liver and bile ducts: very rare: hepatitis, acute hepatic insufficiency, deviation from the norm of liver function indicators.

Disturbances from the skin and subcutaneous tissues: often: subcutaneous bruising; infrequently: skin rash, skin itch, purpura (subcutaneous hemorrhage); very rarely: bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), angioedema, erythematous rash, urticaria, eczema and flat lichen; frequency unknown: drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS-syndrome).

Disturbances from musculoskeletal and connective tissue: very rarely: hemorrhage in the muscles and joints (hemarthrosis), arthralgia, arthritis, myalgia.

Disorders from the kidneys and urinary tract: infrequently: hematuria; very rarely: glomerulonephritis, an increase in the serum creatinine concentration.

General disorders and disorders at the site of administration: often: bleeding from the point of vascular puncture; very rarely: fever.

Laboratory and instrumental data: often: lengthening the time of bleeding, reducing the number of neutrophils, decrease in the number of platelets.

Overdose:

Symptoms: an overdose of clopidogrel may lead to an extension of bleeding time and the development of hemorrhagic complications. In the presence of bleeding, adequate therapy is necessary.

Treatment: when bleeding occurs, appropriate treatment is required. If rapid correction of prolonged bleeding time is necessary, transfusion of platelet mass is recommended. The antidote of clopidogrel is not established.

Interaction:

Anticoagulants for oral administration: simultaneous use of clopidogrel and anticoagulants for oral administration may increase the intensity of bleeding, and therefore, the use of this combination is not recommended.

The use of clopidogrel at a dose of 75 mg per day does not change the pharmacokinetics of warfarin (the substrate of the isoenzyme CYP2C9) or the international normalized ratio (INR) in patients long-treated with warfarin. However, simultaneous use with warfarin increases the risk of bleeding due to its independent additional effect on blood coagulability. Therefore, care should be taken when using warfarin and clopidogrel simultaneously.

Inhibitors of glycoprotein IIb / IIIa: simultaneous use of clopidogrel and glycoprotein inhibitors IIb/IIIbut requires caution in patients with an increased risk of bleeding (with trauma, surgery or other pathological conditions) (see section "Special instructions").

Acetylsalicylic acid: acetylsalicylic acid does not affect clopidogrel-induced platelet aggregation-induced platelet-induced inhibition of ADP, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. Nevertheless, simultaneous administration of 500 mg of acetylsalicylic acid twice a day for one day does not significantly prolong the bleeding time caused by the use of clopidogrel. Pharmacodynamic interaction between clopidogrel and acetylsalicylic acid, possibly, leads to an increased risk of bleeding. Given this, caution should be exercised while taking these medications simultaneously, although in clinical trials patients took combination therapy with clopidogrel and acetylsalicylic acid for one year.

Heparin: according to the clinical study in healthy individuals with the use of clopidogrel did not require a change in the dose of heparin, and also did not change the anticoagulant effect of heparin. Simultaneous use of heparin had no effect on suppression of platelet aggregation with clopidogrel. Possible pharmacodynamic interaction between clopidogrel and heparin, leading to an increased risk of bleeding. Therefore, the simultaneous use of these drugs requires caution.

Thrombolytics: the safety of simultaneous use of clopidogrel, fibrin-specific or fibrin-specific thrombolytics and heparin was evaluated in patients with acute myocardial infarction. The frequency of development of clinically significant bleeding was comparable to that of the simultaneous use of thrombolytics, heparin with acetylsalicylic acid.

Non-steroidal anti-inflammatory drugs (NSAIDs): according to a clinical study involving healthy volunteers, the simultaneous use of clopidogrel and naproxen increased latent gastrointestinal bleeding.However, due to the lack of studies on interactions with other NSAIDs at present, it is not known whether the risk of developing gastrointestinal bleeding increases when used together with other NSAIDs. Therefore, concurrent therapy with NSAIDs, including COX-2 inhibitors, and clopidogrel should be performed with caution (see section "Special instructions").

Inhibitors of the isoenzyme CYP2C19: clopidogrel metabolized to the formation of its active metabolite partially under the action of the isoenzyme CYP2C19. Therefore, drugs that inhibit this isoenzyme can cause a decrease in the concentration of the active metabolite clopidogrel. The clinical significance of this interaction is unknown. Simultaneous application with potent or moderate inhibitors of the CYP2C19 isoenzyme should be avoided. The inhibitors of the isoenzyme CYP2C19 are: omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.

Proton pump inhibitors: nThe use of omeprazole at a dose of 80 mg once a day concomitantly with clopidogrel or with a 12-hour interval between taking twodrugs reduced the systemic exposure (AUC) of the active metabolite of clopidogrel by 45% (after taking a loading dose of clopidogrel) and 40% (after taking a maintenance dose of clopidogrel). The decrease in the AUC of the active metabolite of clopidogrel is associated with a decrease in the degree of inhibition of platelet aggregation (39% after taking a loading dose of clopidogrel and 21% after taking a maintenance dose of clopidogrel). An analogous interaction of clopidogrel with esomeprazole is suggested. In observational and clinical studies, conflicting data on the clinical manifestations of the cardiovascular system with respect to this pharmacokinetic / pharmacodynamic interaction were recorded. You should avoid simultaneous use with omeprazole or esomeprazole.

To inhibitors of the proton pump with minimal inhibiting effect on the isoenzyme CYP2C19 are: pantoprazole and lansoprazole. With the simultaneous use of pantoprazole at a dose of 80 mg once a day, the concentration of the active metabolite of clopidogrel in the blood plasma was reduced by 20% (after taking a loading dose of clopidogrel) and by 14% (after taking a maintenance dose of clopidogrel).This was accompanied by a decrease in the degree of inhibition of platelet aggregation, on average, by 15% and 11%, respectively. Therefore, the simultaneous use of clopidogrel with pantoprazole is possible.

Other medications

In studying the pharmacodynamic and pharmacokinetic interaction of clopidogrel and other drugs, the following is revealed:

- with simultaneous use of clopidogrel with atenolol and / or nifedipine, clinically significant pharmacodynamic interaction was not detected;

- the pharmacodynamic activity of clopidogrel did not change significantly with simultaneous use with phenobarbital, cimetidine or estrogens;

- the pharmacokinetics of digoxin or theophylline did not change;

- antacids do not affect the degree of absorption of clopidogrel;

- phenytoin and tolbutamide can safely be used simultaneously with clopidogrel. It is unlikely that clopidogrel can influence the metabolism of other medicines, such as phenytoin and tolbutamide, as well as NSAIDs, which are metabolized by the action of the CYP2C9 isoenzyme;

- Diuretics, beta-blockers,angiotensin converting enzyme (ACE) inhibitors, slow calcium channel blockers, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptics, hormone replacement therapy: clinical studies have not shown clinically significant adverse interactions.

Special instructions:

During treatment with clopidogrel, especially in the first weeks and / or after the inductionatAcute cardiac procedures / surgical interventions, careful monitoring of patients should be performed to exclude signs of bleeding (including latent). Given the risk of bleeding and hematological adverse events (see the side effect section), when clinical symptoms of possible bleeding occur during treatment, it is necessary to immediately perform a clinical blood test with the determination of activated partial thromboplastin time (APTT), platelet function indicators, with counting the number of platelets and conduct other necessary studies.

Clopidogrel prolongs bleeding time,therefore, it should be used with caution in patients with an increased risk of bleeding due to trauma, surgery and other pathological conditions or diseases in which there is a predisposition to developing bleeding (especially gastrointestinal or intraocular), and patients receiving acetylsalicylic acid, NSAIDs, including COX-2 inhibitors, heparin and glycoprotein inhibitors IIb/IIIa.

The simultaneous use of clopidogrel with warfarin may increase the risk of bleeding (see section "Interaction with other drugs"). Therefore, care should be taken when using warfarin and clopidogrel simultaneously.

If the patient undergoes a planned surgical procedure, and the antiplatelet effect is undesirable, then clopidogrel should be canceled 5-7 days before surgery.

The patient should be informed that taking clopidogrel (as monotherapy or in combination with acetylsalicylic acid) may require more time to stop bleeding. Patients should inform the attending physician about each case of unusual (for localization or duration) bleeding.It is also necessary to inform the doctor about taking clopidogrel if the patient is to have surgery (including dental surgery) or before starting a new medication.

Very rarely, with the use of clopidogrel (sometimes even a short one), there have been cases of thrombotic thrombocytopenic purpura. The condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia, associated with neurologic disorders, impaired renal function and fever. Thrombotic thrombocytopenic purpura is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

During the treatment it is necessary to monitor the function of the liver. In severe violations of the liver should be remembered about the risk of hemorrhagic diathesis. The use of clopidogrel is not recommended for patients with acute ischemic stroke less than 7 days old (no data on use in this state).

Cross-reactive hypersensitivity

Patients should be examined for hypersensitivity to other thienopyridine (eg, ticlopidine, prasugrel), since it is known about cross-reactive hypersensitivity between thienopyridines (see the "Side effect" section). Patients with a hypersensitivity to other thienopyridine in a history should be carefully monitored to identify signs of hypersensitivity to clopidogrel during therapy.

Special information on excipients

Zild® should not be taken in patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome, because contains lactose. The drug Zilt® contains hydrogenated castor oil, which can cause stomach upset and diarrhea in patients.

Effect on the ability to drive transp. cf. and fur:

The drug Zilt® does not significantly affect the ability to drive vehicles or engage in other potentially hazardous activities.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

For 7 or 10 tablets in a contour mesh package (blister) from a combined material

OPA / AL / PVC (polyamide / aluminum foil / polyvinylchloride) and aluminum foil printed lacquered foil.

For 2, 4, 8 or 12 contour packs (blisters) of 7 tablets together with instructions for use are placed in a pack of cardboard.

For 3 or 9 contour packs (blisters) of 10 tablets together with the instructions for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C, in the original packaging.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LS-001229

Date of registration:31.12.2010

The owner of the registration certificate:KRKA-RUS, LLC KRKA-RUS, LLC Russia

Manufacturer: & nbsp

KRKA-RUS, LLC Russia

KRKA, d.d. Slovenia

Representation: & nbspKRKA KRKA Slovenia

Information update date: & nbsp07.08.2015

Illustrated instructions

Instructions

Zilt® (Zyllt®)